Vascular cell adhesion molecule-1 (VCAM-1), a member of the immunoglobulin (Ig) supergene family, is expressed on activated, but not resting, endothelium. The integrin VL4 (a4b1), which is expressed on many cell types including circulating lymphocytes, eosinophils, basophils, and monocytes, but not neutrophils, is the principal receptor for VCAM-1. Antibodies to VCAM-1 or VLA-4 can block the adhesion of these mononuclear leukocytes, as well as melanoma cells, to activated endothelium in vitro. Antibodies to either protein have been effective at inhibiting leukocyte infiltration and preventing tissue damage in several animal models of inflammation. Anti-VLA-4 monoclonal antibodies have been shown to block T-cell emigration in adjuvant-induced arthritis, prevent eosinophil accumulation and bronchoconstriction in models of asthma, and reduce paralysis and inhibit monocyte and lymphocyte infiltration in experimental autoimmune encephalitis (EAE). Anti-VCAM-1 monoclonal antibodies have been shown to prolong the survival time of cardiac allografts. Recent studies have demonstrated that anti-VLA-4 mAbs can prevent insulitis and diabetes in non-obese diabetic mice, and significantly attenuate inflammation in the cotton-top tamarin model of colitis.
Thus, compounds which inhibit the interaction between xcex14-containing integrins and VCAM-1 will be useful as therapeutic agents for the treatment of inflammation resulting from chronic inflammatory diseases such as rheumatoid arthritis, multiple sclerosis (MS), asthma, and inflammatory bowel disease (IBD).
It has been discovered that compounds of the formula: 
and the pharmaceutically acceptable salts and esters thereof wherein X and Y are as defined below, inhibit the binding of VCAM-1 to VLA-4 and are useful in treating inflammation associated with chronicinflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis, (MS), asthma, and inflammatory bowel disease (I BD).
The present invention is directed to the discovery that compounds of the formula: 
and the pharmaceutically acceptable salts and esters thereof, inhibit the binding of VCAM-1 to VLA-4 and are useful in treating inflammation associated with chronic inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis, (MS), asthma, and inflammatory bowel disease (I BD).
In accordance with the invention, X is a group X-1, X-2 or X-3 as described below. Y is a group Y-1, Y-2 or Y-3 as described below.
The group X-1 is of the formula: 
wherein:
R15 is halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl, perfluorolower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkylsulfinyl lower alkyl, lower alkylsulfonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl, aryloxy;
R16 is hydrogen, halogen, nitro, cyano, lower alkyl, OH, perfluorolower alkyl, or lower alkylthio.
The groups R15 and R16 are preferably independently hydrogen, lower alkyl, nitro, halogen (especially chloro or fluoro), perfluoromethyl, or cyano for R16, and lower alkyl, nitro, halogen (especially chloro or fluoro), perfluoromethyl, or cyano for R15.
It is preferred that groups selected as R15, or R15 and R16, be electron-deficient as defined below.
X-2 is a group of the formula: 
wherein Het is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N,O, and S, or
Het is a 9- or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S, and N;
R15 and R16 are as above, and
R30 is hydrogen or lower alkyl; and p is an integer from 0 to 1.
Het is preferably a 5- or 6-membered monocyclic heteroaromatic ring containing 1, 2 or 3 nitrogens, or a nitrogen and a sulfur, or a nitrogen and an oxygen. When Het is a bicyclic heteroaromatic ring, it preferably contains from 1 to 3 nitrogens as the heteroatoms. R15 is preferably, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, perfluorolower alkyl, lower alkylthio, lower alkanoyl, or aryl (especially unsubstituted phenyl); R16 is preferably hydrogen, halogen, nitro, cyano, lower alkyl, perfluoro lower alkyl; and R30, when present, is preferably hydrogen or lower alkyl.
The group X-3 is of the formula: 
wherein:
R18 is aryl, heteroaryl,
R19 is substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkyl, heteroaryl alkyl, and
R20 is substituted or unsubstituted lower alkanoyl or aroyl
R18 is preferably phenyl. R19 is preferably lower alkyl, which is unsubstituted or substituted by pyridyl or phenyl. R20 is preferably lower alkanoyl
Y is a group of formula Y-1, Y-2, or Y-3 wherein:
Y-1 is a group of the formula: 
wherein:
R22 and R23 are independently hydrogen, lower alkyl, lower alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, lower alkanoyl, halogen, or perfluorolower alkyl and at least one of R22 and R23 is other than hydrogen, and
R24 is hydrogen, lower alkyl lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen
Y-2 is a group of the formula 
Het is a five or six membered heteroaromatic ring bonded via a carbon atom wherein said ring contains one, two or three heteroatoms selected from the group consisting of N, O and S and R30 and R31 are independently hydrogen, lower alkyl, cycloalkyl, halogen, cyano, perfluoroalkyl, or aryl and at least one of R30 and R31 is adjacent to the point of attachment, p is an integer of from 0 to 1.
Y-3 is a 3-7 membered ring of the formula: 
wherein:
R25 is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a group of formula R26xe2x80x94(CH2)exe2x80x94, R26 is aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or R26 is a group of formula xe2x80x94NR28R29,
wherein
R28 is H or lower alkyl,
R29 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower akanoylamino, lower alkyl sulfonyl, lower alkylaminocarbonyl, arylaminocarbonyl,
or
R28 and R29 taken together form a 4, 5 or 6-membered saturated carbocyclic ring optionally containing one heteroatom selected from O, S, and N with the carbon atoms in the ring being unsubstituted or substituted by lower alkyl or halogen,
Q is xe2x80x94(CH2)fOxe2x80x94, xe2x80x94(CH2)fSxe2x80x94, xe2x80x94(CH2)fN(R27)xe2x80x94, or xe2x80x94(CH2)fxe2x80x94,
R27 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, e is an integer from 0 to 4, and f is an integer from 0 to 3; the dotted bond is optionally hydrogenated.
This invention is directed to a compound of the formula: 
wherein X is a group of the formula 
wherein:
R15 is halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl perfluorolower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkylsulfinyl lower alkyl, lower alkylsulfonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl, aryloxy;,
R16 is hydrogen, halogen, nitro, cyano, lower alkyl, OH, perfluorolower alkyl, or lower alkylthio; or
X is a group of formula X-2 
wherein Het is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N,O, and S, or
Het is a 9- or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S, and N;
R15 and R16 are as above;
R30 is hydrogen or lower alkyl; and p is an integer from 0 to 1
or X is a group of formula X-3 
wherein:
R18 is aryl, heteroaryl, aryl lower alkyl, heteroaryl lower alkyl
R19 is substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkyl, heteroaryl alkyl, and
R20 is substituted or unsubstituted lower alkanoyl or aroyl;
and Y is a group of formula Y-1 
wherein:
R22 and R23 are independently hydrogen, lower alkyl, lower alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, lower alkanoyl, halogen, or perfluorolower alkyl and at least one of R22 and R23 is other than hydrogen, and
R24 is hydrogen, lower alkyl, lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen;
or Y-2 is a group of the formula: 
Het is a five or six membered heteroaromatic ring bonded via a carbon atom wherein said ring contains one, two or three heteroatoms selected from the group consisting of N, O and S and R30 and R31 are independently hydrogen, lower alkyl, cycloalkyl, halogen, cyano, perfluoroalkyl, or aryl and at least one of R30 and R31 is adjacent to the point of attachment; p is an integer of from 0 to 1;
or Y is a group of formula Y-3 
wherein:
R25 is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a group of formula R26xe2x80x94(CH2)exe2x80x94, R26 is aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or R26 is a group of formula xe2x80x94NR28R29,
wherein
R28 is H or lower alkyl,
R29 is hydrogen, lower alkyl lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower alkanoylamino, lower alkyl sulfonyl, lower alkylaminocarbonyl, arylaminocarbonyl, or R28 and R29 taken together form a 4, 5 or 6-membered saturated carbacyclic ring optionally containing, one heteroatom selected from O, S, and N; with the carbon atoms in the ring being unsubstituted or substituted by lower alkyl or halogen,
Q is xe2x80x94(CH2)fOxe2x80x94, xe2x80x94(CH2)fSxe2x80x94, xe2x80x94(CH2)fN(R27)xe2x80x94, or xe2x80x94(CH2)fxe2x80x94,
R27 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl,
e is an integer from 0 to 4, and
f is an integer from 0 to 3; and the dotted bond is optionally hydrogenated;
and pharmaceutically acceptable salts and esters thereof.
Preferred compounds are as follows:
Compounds where X is a group of the formula 
and Y, R15 and R16 are as in formula 1.
Such compounds where R15 is lower alkyl, nitro, halogen, perfluoromethyl, or cyano and R16 is hydrogen, lower alkyl, nitro, halogen, perfluoromethyl, or cyano, especially where R15 and R16 are independently chloro or fluoro are preferred, especially where X-1 is selected from the group of 
Compounds of formula 1 wherein X is a group of the formula X-2 
and p, Y, R15, R16, and R30 are as in formula 1 (compound A) especially where Het is a 5- or 6-membered monocyclic heteroaromatic ring containing 1, 2 or 3 nitrogens, or a nitrogen and a sulfur, or a nitrogen and an oxygen or where Het is a bicyclic heteroaromatic ring containing from 1 to 3 nitrogens or where R15 is nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, perfluorolower alkyl, lower alkylthio, lower alkanoyl, or aryl, especially where aryl is unsubstituted phenyl. In compound A R16 may be hydrogen, halogen, nitro, cyano, lower alkyl, perfluoro lower alkyl; and R30 is hydrogen or lower alkyl, or in compound A Het may be a 6 membered monocyclic heteroaromatic ring containing 1 or 2 nitrogens or a 10 membered bicyclic heteroaromatic ring containing one nitrogen, R15 is lower alkyl, or perfluoroalkyl and R16 is hydrogen, lower alkyl, or perfluoroalkyl, and R30 is absent. In compound A, X-2 may be selected from the group of 
Compounds of formula 1 wherein X is a group of formula X-3 
and Y, R18, R19, and R20 are as in formula 1 (compound B). In compound B, it is preferred that R18 is phenyl. In compound B it is also preferred that R19 is lower alkyl which is unsubstituted or substituted by pyridyl or phenyl. In compound B it is also preferred that R20 is substituted or unsubsituted lower alkanoyl. In compound B it is also preferred that R18 is phenyl, R19 is lower alkyl which is unsubstituted or substituted by pyridyl or phenyl and R20 is lower alkanoyl. In compound B it is preferred that R18 is phenyl which is unsubstituted or substituted by halogen or lower alkoxy; R19 is phenyl lower alkyl which is unsubstituted or substituted by lower alkoxy, pyridyl lower alkyl, or lower alkyl; and R20 is substituted or unsubstituted lower alkanoyl.
In this latter compound, it is preferred that X-3 is selected from the group of 
Compounds of formula 1 where Y is a group of formula 
and X, R22, R23, and R24 are as in formula 1 (compound C). It is preferred for compound C that R22 and R23 are lower alkyl, trifluoromethyl, or halogen and R24 is hydrogen, lower alkyl, lower alkoxy, or halogen, especially when Y-1 is selected from the group of 
Compounds of formula 1 wherein Y is a group of the formula Y-2 
and p, X, Het, R30 and R31, are as in formula 1 (compound D). It is preferred for compound D that Het is a 6 membered heteroaromatic ring, especially where the heteroatom is N, and preferably where Y-2 is selected from the group of 
Compounds of formula 1 where Y is a group of formula Y-3 
and Y, R25 and Q are as in formula 1, and the dotted bond can be optionally hydrogenated (compound E). It is preferred for compound E that Y-3 is selected from the group of 
A compound of formula 1 wherein X is a group of the formula X-1 and Y is a group of the formula Y-1.
A compound of formula 1 wherein X is a group of the formula X-1 and Y is a group of the 
formula Y-2.
A compound of formula 1 wherein X is a group of the formula X-1 Y is a group of the formula Y-3 wherein R15, R16, R25 and Q are as above; and the dotted bond can be optionally hydrogenated.
A compound of formula 1 wherein X is a group of the formula X-2 and Y is a group of the formula Y-1.
A compound of formula 1 wherein X is a group of the formula X-2 and Y is a group of the formula Y-2.
A compound of formula 1 wherein X is a group of the formula X-2 and Y is a group of the 
formula Y-3 wherein R15, R16, R25, R30, Q and p are as above and the dotted bond can be optionally hydrogenated.
A compound of formula 1 where X is a group of the formula X-3 and Y is a group of the formula Y-1.
A compound of formula 1 wherein X is a group of the formula X-3 and Y is a group of the formula Y-2.
A compound of formula 1 wherein X is a group of the formula X-3 and Y is a group of the formula Y-3 where R18, R19, R20, R25, and Q are as above and the dotted bond can be optionally hydrogenated.
A compound of claim 1 wherein X is a group of the formula X-1 
wherein R16 is in the ortho position and is hydrogen, lower alkyl, nitro, cyano, halogen, lower alkylthio, perfluoroloweralkyl and R15 is lower alkyl, nitro, cyano, halogen, lower alkylsulfonyl, perfluoroloweralkyl, and Y is a group of the formula Y-1 
where R22 is hydrogen, halogen, trifluoroalkyl, or lower alkyl and R23 is halogen, trifluoroalkyl, or lower alkyl, and R24 is hydrogen or Y is a group of the formula Y-3 
wherein Q is as above and the dotted bond can be optionally hydrogenated; R25 is R26xe2x80x94(CH2); e is 2-4 and R26 is azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or lower alkylthio or R25 is NHR29 where R29 is lower alkanoyl or lower alkylamino carbonyl (compound E).
In compound E it is preferred that X is a group of the formula X-1 
wherein R16 is in the ortho position and is hydrogen, lower alkyl, nitro, cyano, halogen, lower alkylthio, perfluoroloweralkyl and R15 is lower alkyl, nitro, cyano, halogen, lower alkylsulfonyl, perfluoroloweralkyl; and Y is a group of the formula Y-1 
where R22 is hydrogen, halogen, or lower alkyl and R23 is halogen or lower alkyl, and R24 is hydrogen, especially where R16 is hydrogen or halogen and R15 is halogen; R22 is hydrogen, halogen, ethyl, or methyl and R23 is halogen, ethyl, or methyl, and additionally where R16 is in the ortho position and R15 and R16 are both chlorine, and R22 is methyl and R23 is chlorine or ethyl. An example of such a compound is 4[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-chloro-6-methylphenyl)thioxomethyl]-L-phenylalanine.
In compound E it is also preferred that X is a group of the formula X-1 
wherein R16 is in the ortho position and is hydrogen, lower alkyl, nitro, cyano, halogen, lower alkylthio, perfluoroloweralkyl and R15 is lower alkyl, nitro, cyano, halogen, lower alkylsulfonyl, perfluoroloweralkyl; and Y is a group of the formula Y-3 
which is a four to six membered cycloalkyl ring, R25 is R26xe2x80x94(CH2)e-; e is 2-4 and R26 is azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or lower alkylthio; and the dotted bond is hydrogenated. In such a compound it is preferred that R16 is hydrogen or halogen and R15 is halogen; and Y-3 is a four or five membered ring and R26 is lower alkoxy, lower alkyl sulfonyl, lower alkyl sulfinyl, or lower alkylthio, especially where R16 is in the ortho position and R15 and R16 are both chlorine, and R26 is lower alkyl sulfonyl or lower alkylthio. An example of such a compound is 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[(4-methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine.
For another preferred compound E X is a group of the formula X-1 
where R16 is hydrogen or halogen and R15 is halogen and Y is a group of the formula Y-1 
where R22 is hydrogen, halogen, ethyl, or methyl and R23 is halogen, ethyl, or methyl and R24 is hydrogen or Y is a group of the formula Y-3 
where Y-3 is a four or five membered ring, R25 is as in claim 39 and R26 is lower alkoxy, lower alkyl sulfonyl, lower alkyl sulfinyl, or lower alkylthio, and the dotted bond is optionally hydrogenated. For such a compound it is preferred that R16 is in the ortho position and R15 and R16 are both chlorine, and when Y is Y-1 then R22 is methyl and R23 is chlorine or ethyl and when Y is Y-3, Y-3 is a four or five membered ring and R26 is lower alkyl sulfonyl or lower alkylthio.
A compound of formula 1 wherein Y is as in formula 1 and X is X-1 
where R15 is ortho and is halogen, lower alkyl, or perfluoroalkyl and R16 is hydrogen, halogen, lower alkyl, or perfluoroalkyl (compound F).
For compound F it is preferred that R15 is chlorine and R16 is hydrogen or chlorine.
A compound of formula 1 wherein Y is as in formula 1 and X is X-2 where Het is pyridine or pyrimidine and R15 is lower alkyl or perfluoroalkyl R16, and R20 are hydrogen, lower alkyl, or perfluoroalkyl (compound G).
A compound of formula 1 wherein Y is as in formula 1 and X is X-3 where R19 is pyridinyl lower alkyl or phenyl lower alkyl, R20 is lower alkanoyl, and R18 is phenyl (compound H).
A compound of formula 1 where X is as in formula 1 and Y is Y-1 where R22 is hydrogen or lower alkyl, R23 is halogen, lower alkyl, or perfluoroalkyl, and R24 is hydrogen, especially where R22 is hydrogen or methyl and R23 is halogen, ethyl, or trifluoromethyl.
A compound of formula 1 wherein X is as in formula 1 and Y is Y-3 which is a four to six membered cycloalkyl ring, R25 is R26xe2x80x94(CH2)e-, e is 2-4, and R26 is alkoxy, lower alkyl sulfonyl, loweralkylthio, or NHR29 where R29 is loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is hydrogenated. It is preferred that R26 is methoxy, methyl sulfonyl, or methylthio.
A preferred compound F has Y is Y-1 where R22 is hydrogen or lower alkyl, R23 is halogen, lower alkyl, or perfluoroalkyl, and R24 is hydrogen. It is preferred that R15 is chlorine and R16 is hydrogen or chlorine. Examples are
4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-bromophenyl)thioxomethyl]-L-phenylalanine;
4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[(2-ethyl-6-methylphenyl)thioxomethyl]L-phenylalanine.
4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[(2-fluorophenyl)thioxomethyl]-L-phenylalanine.
4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[[2-(trifluoromethyl)phenyl]thioxomethyl]-L-phenylalanine.
In a preferred compound G, Y is Y-1 where R22 is hydrogen or lower alkyl, R23 is halogen, lower alkyl, or perfluoroalkyl, and R24 is hydrogen.
In a preferred compound H, Y is Y-1 where R22 is hydrogen or lower alkyl, R23 is halogen, lower alkyl, or perfluoroalkyl, and R24 is hydrogen. An example of such a compound is 4-[(2S,4R)-3-acetyl-2-phenyl-4-[(3-pyridinyl)methyl]-5-oxo-imidazolidin-1-yl]-N-[(2-ethyl-6-methylpheny)thioxomethyl]-L-phenylalanine.
In a preferred compound F, Y is Y-3 which is a four to six membered cycloalkyl ring, R25 
is R26xe2x80x94(CH2)e-, e is 2-4, and R26 is alkoxy, lower alkyl sulfonyl, loweralkylthio, or NHR29 where R29 is loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is hydrogenated. It is preferred that R15 is chlorine and R16 is hydrogen or chlorine. Examples of such compounds are
4-[[2,6-dichlorophenyl)carbonyl]amino-N-[[1-[2-(acetylamino)ethyl]cyclopentyl]thioxomethyl]-L-phenylalanine.
[[1-[2-[[(methylamino)carbonyl]amino]ethyl]cyclopentyl]thioxomethyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]L-phenylalanine.
4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[[1-(2-methoxyethyl)cyclopentyl]thioxomethyl]-L-phenylalanine.
4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[[1-[(4-methylsulfonyl)butyl]cyclobutyl]thioxomethyl]-L-phenylalanine.
4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[[1-(3-methylthio)propyl]cyclobutyl]thioxomethyl]-L-phenylalanine.
4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[[1-(3-methylsulfonyl)propyl]cyclobutyl]thioxomethyl]-L-phenylalanine.
It is preferred that R26 is methoxy, methyl sulfonyl, or methyl thio, especially where R15 is chlorine and R16 is hydrogen or chlorine.
A preferred compound G wherein Y is Y-3 which is a four to six membered cycloalkyl ring, R25 is R26xe2x80x94(CH2)e-, e is 2-4, and R26 is alkoxy, lower alkyl sulfonyl, loweralkylthio, or NHR29 where R29 is loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is hydrogenated. Preferably R26 is methoxy, methyl sulfonyl, or methyl thio. Examples are
4-[(2,6-dimethyl-3-pyridinylcarbonyl)amino]-N-[[1-[(4-methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine.
4-[[[4-(trifluoromethyl)-5-pyrimidinyl]carbonyl]amino]-N-[[1-(4-methylsulfonyl)butyl]cyclobutyl]thioxomethyl]-L-phenylalanine.
4-[[(2,4-dimethyl-6-trifluoromethyl-3-pyridinyl)carbonyl]amino]-N-[[1-[(4-methylsulfonyl)butyl]cyclobutyl]thioxomethyl]-L-phenylalanine.
In a preferred compound H, Y is Y-3 which is a four to six membered cycloalkyl ring, R25 
is R26xe2x80x94(CH2)e-, e is 2-4, and R26 is alkoxy, lower alkyl sulfonyl, loweralkylthio, or NHR29 where R29 is loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is optionally hydrogenated, especially where R26 is methoxy, methyl sulfonyl, or methyl thio. Examples are
4-[(2S,4R)-3-acetyl-2-phenyl-4-[(3-phenyl)methyl]-5-oxo-imidazolidin-1-yl]-N-[[(4-methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine
4-[(2R,4R)-3-acetyl-2-phenyl-4-[(3-phenyl)methyl]-5-oxo-imidazolidin-1-yl]-N-[[(4-methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine.
As used in this specification, the terms are defined as follows:
The term xe2x80x9chalogenxe2x80x9d means bromine, chlorine, fluorine, or iodine, and the term xe2x80x9chaloxe2x80x9d means a halogen substituent.
The term xe2x80x9cperfluoroxe2x80x9d means complete substitution of all hydrogen atoms with fluoro substituted, as in perfluoro lower alkyl, perfluoroloweralkanoyl and perfluoroalkanoylamino. An example is trifluoromethyl.
The term xe2x80x9clower alkylxe2x80x9d, alone or in combination (for example as part of lower alkanoyl, below), means a straight-chain or branched-chain alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl and the like. Lower alkyl groups may be unsubstituted or substituted by one or more groups selected independently from cycloalkyl, nitro, aryloxy, aryl (preferably phenyl or pyridyl), hydroxy (lower alkylhydroxy or hydroxylower alkyl), halogen, cyano, lower alkoxy (alkoxy lower alkyl or lower alkyl alkoxy), lower alkanoyl, lower alkylthio (lower alkylthio lower alkyl) sulfinyl (lower alkyl sulfinyl), sulfinyl lower alkyl (lower alkyl sulfinyl lower alkyl) sulfonyl (lower alkyl sulfonyl), sulfonyl lower alkyl (lower alkyl sulfonyl lower alkyl) perfluoro (perfluoro lower alkyl) and substituted amino such as aminosulfonyl (lower alkyl aminosulfonyl) or aminocarbonyl (lower alkyl aminocarbonyl). Examples of substituted lower alkyl groups include 2-hydroxylethyl, 3-oxobutyl, cyanomethyl, and 2-nitropropyl. The term xe2x80x9clower alkylthioxe2x80x9d means a lower alkyl group bonded through a divalent sulfur atom, for example, a methyl mercapto or a isopropyl mercapto group.
The term xe2x80x9ccycloalkylxe2x80x9d means an unsubstituted or substituted 3- to 7-membered carbacyclic ring. Substituents useful in accordance with the present invention are hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkyl, aroyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, aryl, heteroaryl and substituted amino.
The term xe2x80x9clower alkoxyxe2x80x9d means a lower alkyl group as defined above, bonded through an oxygen atom. Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.
The term xe2x80x9clower alkenylxe2x80x9d means a nonaromatic partially unsaturated hydrocarbon chain containing at least one double bond, which is preferably 1-10 and more preferably 1-6 carbons in length. The group may be unsubstituted, or substituted with conventional substituents, preferably fluoro. Examples are vinyl, allyl, dimethylallyl, butenyl, isobutenyl, pentenyl.
The term xe2x80x9carylxe2x80x9d means a mono- or bicylic aromatic group, such as phenyl or naphthyl, which is unsubstituted or substituted by conventional substituent groups. Preferred substituents are lower alkyl, lower alkoxy, hydroxy lower alkyl, hydroxy, hydroxyalkoxy, halogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano, nitro, perfluoroalkyl, alkanoyl, aroyl, aryl alkynyl, lower alkynyl, aminoalkylcarbonyl (arylaminocarbonyl) and lower alkanoylamino. The especially preferred substituents are lower alkyl, hydroxy, and perfluoro lower alkyl. Examples of aryl groups that may be used in accordance with this invention are phenyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, m-hydroxy phenyl, m-methylthiophenyl, 2-methyl-5-nitrophenyl, 2,6-dichlorophenyl, 1-naphthyl and the like.
The term xe2x80x9carylalkylxe2x80x9d means a lower alkyl group as hereinbefore defined in which one or more hydrogen atoms is/are replaced by an aryl group as herein defined. Any conventional aralkyl may be used in accordance with this invention, such as benzyl and the like. Similarly, the term xe2x80x9cheteroarylalkylxe2x80x9d is the same as an arylalkyl group except that there is a heteroaryl group as defined below in place of an aryl group. Either of these groups may be unsubstituted, or may be substituted on the ring portion with conventional substituents such as
The term xe2x80x9cheteroarylxe2x80x9d means an unsubstituted or substituted 5- or 6-membered monocyclic hetereoaromatic ring or a 9- or 10-membered bicyclic hetereoaromatic ring containing 1, 2, 3 or 4 hetereoatoms which are independently N, S or O. Examples of hetereoaryl rings are pyridine, benzimidazole, indole, imidazole, thiophene, isoquinoline, quinzoline and the like. Substituents as defined above for xe2x80x9carylxe2x80x9d apply equally here in the definition of heteroaryl. The term xe2x80x9cheteroaromatic ringxe2x80x9d may be used interchangeably with the term heteroaryl.
The term xe2x80x9clower alkoxycarbonylxe2x80x9d means a lower alkoxy group bonded via a carbonyl group. Examples of alkoxycarbonyl groups are ethoxycarbonyl and the like.
The term xe2x80x9clower alkylcarbonyloxyxe2x80x9d means lower alkylcarbonyloxy groups bonded via an oxygen atom, for example an acetoxy group.
The term xe2x80x9clower alkanoylxe2x80x9d means lower alkyl groups bonded via a carbonyl group and embraces in the sense of the foregoing definition groups such as acetyl, propionyl and the like. Lower alkanoyl groups may be unsubstituted, or substituted with conventional substituents such as alkoxy, lower alkyl, hydroxy, aryl, and hetereoaryl.
The term xe2x80x9clower alkylcarbonylaminoxe2x80x9d means lower alkylcarbonyl groups bonded via a nitrogen atom, such as acetylamino.
The term xe2x80x9caroylxe2x80x9d means an mono- or bicyclic aryl or heteroaryl group bonded via a carbonyl group. Examples of aroyl groups are benzoyl, 3-cyanobenzoyl, 2-naphthyl and the like. Aroyl groups may be unsubstituted, or substituted with conventional substituents such as
The term xe2x80x9caryloxyxe2x80x9d means an aryl group, as hereinbefore defined, which is bonded via an oxygen atom. The preferred aryloxy group is phenoxy.
The term xe2x80x9celectron-deficient substituentxe2x80x9d means a substituent on an aromatic or heteroaromatic ring which has a positive Hammett sigma values as defined for example in Jerry March, Advanced Organic Chemistry, 2nd Edition, McGraw Hill, 1977, page 246-253. Typical electron withdrawing groups are cyano, nitro, chloro, alkoxycarbonyl lower alkyl sulfonyl, and aminocarbonyl.
In the compound of formula 1, Y is preferably the group Y-1 whereby the invention comprises a compound of the formula: 
wherein X, R22, R23 and R24 are as above.
In the group Y-1, R22 and R23 are preferably lower alkyl or halogen and R24 is preferably hydrogen.
Among the groups Y-1, when R23 is lower-alkyl or halogen, Y-1 is preferably: 
When Y is a group Y-2, Y is preferably: 
When Y is a group Y-3, Y is preferably: 
The especially preferred groups X-1 are of the formula: 
The especially preferred groups X-2 are of the formula: 
The especially preferred groups X-3 are of the formula: 
The compounds of the invention can exist as stereoisomers and diastereomers, all of which are encompassed within the scope of the present invention.
The compounds of the invention inhibit the binding of VCAM-1 and fibronectin to VLA-4 on circulating lymphocytes, eosinophils, basophils, and monocytes (xe2x80x9cVLA-4-expressing cellsxe2x80x9d). The binding of VCAM-1 and fibronectin to VLA-4 on such cells is known to be implicated in certain disease states, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and particularly in the binding of eosinophils to pulmonary endothelium which contributes to the cause of the pulmonary inflammation which occurs in asthma. Thus, the compounds of the present invention would be useful for the treatment of asthma.
On the basis of their capability of inhibiting binding of VCAM-1 and fibronectin to VLA-4 on circulating lymphocytes, eosinophils, basophils, and monocytes, the compounds of the invention can be used as medicament for the treatment of disorders which are known to be associated with such binding. Examples of such disorders are rheumatoid arthritis, multiple sclerosis, asthma, and inflammatory bowel disease. The compounds of the invention are preferably used in the treatment of diseases which involve pulmonary inflammation, such as asthma. The pulmonary inflammation, which occurs in asthma, is related to eosinophil infiltration into the lungs wherein the eosinophils bind to endothelium which has been activated by some asthma-triggering event or substance.
Furthermore, compounds of the invention also inhibit the binding of VCAM-1 and MadCAM to the cellular receptor alpha4-beta7, also known as LPAM, which is expressed on lymphocytes, eosinophils and T-cells. While the precise role of alpha4-beta7 interaction with various ligands in inflammatory conditions such as asthma is not completely understood, compounds of the invention which inhibit both alpha4-beta1 and alpha4-beta7 receptor binding are particularly effective in animal models of asthma. Furthermore work with monoclonal antibodies to alpha4-beta7 indicate that compounds which inhibit alpha4-beta7 binding to MadCAM or VCAM are useful for the treatment of inflammatory bowel disease. They would also be useful in the treatment of other diseases in which such binding is implicated as a cause of disease damage or symptoms.
The compounds of the invention can be administered orally, rectally, or parentally, e.g., intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually, or as opthalmalogical preparations, or as an aerosol in the case of pulmonary inflammation. Capsules, tablets, suspensions or solutions for oral administration, suppositories, injection solutions, eye drops, salves or spray solutions are examples of administration forms.
Intravenous, intramuscular, oral or inhalation administration is a preferred form of use. The dosages in which the compounds of the invention are administered in effective amounts depending on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of administration. Dosages may be determined by any conventional means, e.g., by dose-limiting clinical trials. Thus, the invention further comprises a method of treating a host suffering from a disease in which VCAM-1 of fibronectin binding to VLA-4-expressing cells is a causative factor in the disease symptoms or damage by administering an amount of a compound of the invention sufficient to inhibit VCAM-1 or fibronectin binding to VLA-4-expressing cells so that said symptoms or said damage is reduced. In general, dosages of about 0.1-100 mg/kg body weight per day are preferred, with dosages of 1-25 mg/kg per day being particularly preferred, and dosages of 1-10 mg/kg body weight per day being especially preferred.
The invention further comprises pharmaceutical compositions which contain a pharmaceutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. Such compositions may be formulated by any conventional means. Tablets or granulates can contain a series of binders, fillers, carriers or diluents. Liquid compositions can be, for example, in the form of a sterile water-miscible solution. Capsules can contain a filler or thickener in addition to the active ingredient. Furthermore, flavor-improving additives as well as substances usually used as preserving, stabilizing, moisture-retaining and emulsifying agents as well as salts for varying the osmotic pressure, buffers and other additives can also be present.
The previously mentioned carrier materials and diluents can comprise any conventional pharmaceutically acceptable organic or inorganic substances, e.g., water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like.
Oral unit dosage forms, such as tablets and capsules, preferably contain from 25 mg to 1000 mg of a compound of the invention.
The compounds of the present invention may be prepared by any conventional means. In reaction Scheme 1, a 4-nitro-L-phenylalanine derivative of formula 1 in which R1 is lower alkyl, which is a known compound or readily prepared by conventional means, is acylated with a benzoic acid derivative of formula 2 in which R2 hydrogen, lower alkyl, lower alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, lower alkanoyl, halogen, or perfluorolower alkyl, R3 is hydrogen, halogen or lower alkyl and R4 is hydrogen, lower alkyl, lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen, using conventional means for amide bond formation. For example, a compound of formula 2 may be converted to the corresponding acid chloride and condensed with a compound of formula 1 in the presence of a proton acceptor such as a tertiary alkylamine. Alternatively compound 1 can be coupled with a carboxylic acid of formula 2 using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0xc2x0 C. and room temperature to give a compound of formula 3.
Conversion of the compound of formula 3 to the corresponding thioamide of formula 4 can be carried out by treatment with Lawesson""s reagent which is [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide]. The procedure is standard and has been described in detail. See for example, Scheibey, S., Pedersen, B. S., Lawesson, S.-O. Bull Soc. Chim. Belg. 1978 87, 229 and Cava, M. P., Levinson, M. I., Tetrahedron 1985, 41, 5061. The nitro group of the compound of formula 4 may be reduced to the corresponding amine by any of the conventional means which are compatible with thioamides. One convenient procedure employs zinc dust as the reducing agent in the presence of methanol, ammonium chloride and water at a temperature of from 35 to 60xc2x0 C. to give a compound of formula 5. Acylation of this compound with an aryl- or heteroaryl carboxylic acid of formula 6 using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0xc2x0 C. and room temperature gives a compound of formula 7. In certain cases, for example with hindered carboxylic acids 6, it may be advantageous to form the corresponding acid halide and react it with the amine of formula 5, typically in the presence of a slight excess of a base such as a tertiary amine or 4-(dimethylamino)pyridine. The carboxylic acid of formula 6 may be substituted by halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl, perfluorolower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, alkylthio lower alkyl, alkylsulfinyl lower alkyl, alkylsufonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl, aryloxy. Where appropriate, it may also incorporate suitably protected reactive functionalities which must be removed to permit final conversion into compounds of the invention. The choice and use of such groups will be apparent to those skilled in the art. Guidance for the selection and use of protecting groups is provided in standard reference works, for example: xe2x80x9cT. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, Wiley Interscience, New York, 1991. The ester moiety of compound 7 can generally be cleaved to the corresponding carboxylic acid by treatment with all alkali metal hdyroxide, for example, lithium hydroxide in aqueous methanol at a temperature of from room temperature to 50xc2x0 C. Depending on the nature of R1, alternative procedures may be preferred. The choice of conditions for ester cleavage in the presence of functionalities such as thioamides is well known to those skilled in the art. 
Ortho-substituted benzoic acid derivatives which are not commercially available can be prepared by conventional means. For example ortho-substituted aryl iodides or triflates may be carbonylated in the presence of carbon monoxide and a suitable palladium catalyst. The preparation of such iodide or triflate intermediates is dependent on the particular substitution pattern desired and they may be obtained by direct iodination or diazotization of an aniline followed by treatment with a source of iodide for example, potassium iodide. Triflates may be derived from the corresponding phenols by conventional means such as treatment with trifluoromehane sulfonic anhydride in the presence of a base such as triethylamine or diisopropylethylamine in an inert solvent. Other means of obtaining ortho-substituted benzoic acids involves treatment of an 2-methoxyphenyloxazoline derivative such as 9 with an alkyl Grignard reagent followed by hydrolysis of the oxazoline ring following the general procedure described by Meyers, A. I., Gabel, R., Mihelick, E. D, J. Org. Chem. 1978, 43, 1372-1379., to give an acid of formula 10. 2- or 2,6-Disubstituted benzonitriles also serve as convenient precursors to the corresponsing benzoic acids. In the case of highly hindered nitrites, for example 2-chloro-6-methylbenzonitrile, conventional hydrolysis under acidic or basic conditions is difficult and better results are obtained by DIBAL reduction to the corresponding benzaldehyde followed by oxidation using a sodium chlorite/hydroperoxide oxidizing reagent. 
Employing essentially the same procedures described in Scheme 1, utilizing a heteroaromatic carboxylic acid in place of 2, one can prepare compounds of formula 11. 
For the synthesis of analogues a branched chain or cycloalkyl moiety, a similar procedure to that described in scheme 1 can be employed starting with the appropriate branched chain or cycloalkyl carboxylic acid of formula 12. In this case, R6 represents is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a substituted lower alkyl group wherein the substituents may be chosen from aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkylthio, lower alkyl sulfonyl, perfluoro lower alkanoyl, nitro, or a protected amino group. The amine protecting group must be chosen to be compatible with the reagents needed to convert carboxamides to thioamides. Carbamates, for example, the tert-butoxycarbonyl moiety are suitable. As appropriate, these protecting groups may be removed by conventional means later in the synthesis and the resulting free amine can be further functionalized utilizing standard methods. For example, the amine can be acylated by treatment with the appropriate anhydride, isocyanate or acid halide. 
The synthesis of imidazolidinones of formula 21 is described in reaction scheme 3. An amninophenylalanine derivative of structure 13 in which R6 is aryl, heteroaryl, branched chain alkyl or derived from a compound of formula 12, and R7 is lower alkyl, is coupled with a N-protected alpha-amino acid of formula 14, in which R8 can be a natural or unnatural, D- or L-xcex1-amino acid side chain and R9 is a nitrogen protecting group of the type conventionally used in peptide chemistry, for example, a Fmoc group, using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0xc2x0 C. and room temperature to give a compound of formula 15. Depending on the nature of protecting group R9, an appropriate deprotection method is employed to give compound of formula 16. In the case of the protecting group R9 is Fmoc group, it may be removed from 15 using standard base treatment well known to those practicing peptide chemistry, for example with piperidine in DMF, to afford an amine of formula 16. The compound 16 can then react with an aldehyde 17, in which R10 is lower alkyl, aryl, or aryl lower alkyl, in the presence of a water scavenger such as 4 xc3x85 molecular sieves in an appropriate solvent such as dichloromethane or THF at 25-60xc2x0 C. to give an imine of formula 18. The imine 18 may then be treated with an acylating agent such as the acyl chloride of formula 19 in which R11 can be an alkyl or aryl group in the presence of a base such DIPEA or DBU in an appropriate solvent such as dichloromethane or THF at 25-60xc2x0 C. to give an acyl imidazolidinone of formula 20. Alternatively, other reactive acylating groups such as acid anhydrides or mixed anhydrides may be employed in this reaction. Compound 20 may be converted to a compound of the invention by an appropriate hydrolysis procedure, for example by hydrolysis by treatment with an alkali metal hydroxide, for example sodium hydroxide in aqueous alcohol to give, after acidification, a carboxylic acid of formula 21. 
General Melting points were taken on a Thomas-Hoover apparatus and are uncorrected. Optical rotations were determined with a Perkin-Elmer model 241 polarimeter. 1H-NMR spectra were recorded with Varian XL-200 and Unityplus 400 MHz spectrometers, using tetramethylsilane (TMS) as internal standard. Electron impact (EI, 70 ev) and fast atom bombardment (FAB) mass spectra were taken on VG Autospec or VG 70E-HF mass spectrometers. Silica gel used for column chromatography was Mallinkrodt SiliCar 230-400 mesh silica gel for flash chromatography; columns were run under a 0-5 psi head of nitrogen to assist flow. Thin layer chromatograms were run on glass thin layer plates coated with silica gel as supplied by E. Merck (E. Merck #1.05719) and were visualized by viewing under 254 nm UV light in a view box, by exposure to I2 vapor, or by spraying with either phosphomolybdic acid (PMA) in aqueous ethanol, or after exposure to Cl2, with a 4,4xe2x80x2-tetramethyldiaminodiphenylmethane reagent prepared according to E. Von Arx, M. Faupel and M Brugger, J. Chromatography, 1976, 120, 224-228.
Reversed phase high pressure liquid chromatography (RP-HPLC) was carried out using either a Waters Delta Prep 4000 employing a 3xc3x9730 cm, Waters Delta Pak 15 xcexcM C-18 column at a flow of 40 mL/min employing a gradient of acetonitrile:water (each containing 0.75% TFA) typically from 5 to 95% acetonitrile over 35-40 min or a Rainin HPLC employing a 41.4xc3x97300 mm, 8 xcexcM, Dynamax(trademark) C-18 column at a flow of 49 mL/min and a similar gradient of acetonitrile:water as noted above. HPLC conditions are typically described in the format (5-95-35-214); this refers to a linear gradient of from 5% to 95% acetonitrile in water over 35 min while monitoring the effluent with a UV detector set to a wavelength of 214 nM.
Methylene chloride (dichloromethane), 2-propanol, DMF, THF, toluene, hexane, ether, and methanol, were Fisher reagent grade and were used without additional purification except as noted, acetonitrile was Fisher hplc grade and was used as is.
Definitions:
THF is tetrahydrofuran,
DMF is N,N-dimethylformamide,
HOBT is 1-hydroxybenzotriazole,
BOP is [(benzotriazole-1-yl)oxy]tris-(dimethylamino)phosphonium hexafluorophosphate,
HATU is O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
HBTU is O-benzotriazole-N,N,Nxe2x80x2,Nxe2x80x2,-tetramethyluronium hexafluorophosphate,
DIPEA is diisopropylethylamine,
DMAP is 4-(N,N-dimethylamino)pyridine
DPPA is diphenylphosphoryl azide
DPPP is 1,3-bis(diphenylphosphino)propane
DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene
NaH is sodium hydride
brine is saturated aqueous sodium chloride solution
TLC is thin layer chromatography
LDA is lithium diisopropylamide
BOP-Cl is bis(2-oxo-3-oxazolidinyl)phosphinic chloride
NMP is N-methyl pyrrolidinone
Lawesson""s reagent is [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide]